Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis
The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been impli...
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| Language: | English |
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Elsevier
2025-02-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825000453 |
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| author | Jiaqi Yao Yuhong Jiang Pengcheng Zhang Yifan Miao Xiajia Wu Hang Lei Zhijun Xie Yong Tian Xianlin Zhao Juan Li Lv Zhu Meihua Wan Wenfu Tang |
| author_facet | Jiaqi Yao Yuhong Jiang Pengcheng Zhang Yifan Miao Xiajia Wu Hang Lei Zhijun Xie Yong Tian Xianlin Zhao Juan Li Lv Zhu Meihua Wan Wenfu Tang |
| author_sort | Jiaqi Yao |
| collection | DOAJ |
| description | The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been implicated in the development of various diseases, whereas its involvement in the progression of AP remains unclear. This study aims to investigate the role of HINT2 in AP. HINT2 expression in pancreatic tissues was significantly downregulated after AP. The results of glutathione-S-transferase (GST) pull-down and proteomics analyses revealed the involvement of HINT2 in regulating mitochondrial oxidative phosphorylation (OXPHOS) in AP mice. Moreover, lentivirus-mediated HINT2 overexpression not only alleviated AP-induced ATP depletion, but also relieved inflammatory responses and cell necrosis. Mechanistically, HINT2 interacted with cytochrome C oxidase II (MTCO2) to promote mitochondrial OXPHOS, thereby reducing ROS accumulation and inhibiting the activation of inflammatory signaling pathway. Besides, HINT2 act as a direct pharmacological target of Emo to elicit protective effects on AP. Importantly, Emo upregulates the expression of HINT2 and OXPHOS complex proteins and enhances the interaction between HINT2 and MTCO2. Furthermore, CRISPR/Cas9-mediated HINT2 knockout significantly impaired the protective effects of Emo against AP-induced mitochondrial energy metabolism disorders, inflammatory responses, and acinar cell necrosis. Overall, these results uncover a previously unexplored role for HINT2 in maintaining mitochondrial energy metabolism in pancreatic acinar cells and reveals novel mechanism and target for Emo-mediated AP remission. |
| format | Article |
| id | doaj-art-e451e120cb76453d9fe3a2ae3f40837b |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-e451e120cb76453d9fe3a2ae3f40837b2025-02-08T04:59:53ZengElsevierPharmacological Research1096-11862025-02-01212107620Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitisJiaqi Yao0Yuhong Jiang1Pengcheng Zhang2Yifan Miao3Xiajia Wu4Hang Lei5Zhijun Xie6Yong Tian7Xianlin Zhao8Juan Li9Lv Zhu10Meihua Wan11Wenfu Tang12Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Emergency Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province 610075, ChinaInstitute of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China; Digestive Department, The First People’s Hospital of Shuangliu District, Chengdu, ChinaDepartment of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, China; Corresponding author.The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been implicated in the development of various diseases, whereas its involvement in the progression of AP remains unclear. This study aims to investigate the role of HINT2 in AP. HINT2 expression in pancreatic tissues was significantly downregulated after AP. The results of glutathione-S-transferase (GST) pull-down and proteomics analyses revealed the involvement of HINT2 in regulating mitochondrial oxidative phosphorylation (OXPHOS) in AP mice. Moreover, lentivirus-mediated HINT2 overexpression not only alleviated AP-induced ATP depletion, but also relieved inflammatory responses and cell necrosis. Mechanistically, HINT2 interacted with cytochrome C oxidase II (MTCO2) to promote mitochondrial OXPHOS, thereby reducing ROS accumulation and inhibiting the activation of inflammatory signaling pathway. Besides, HINT2 act as a direct pharmacological target of Emo to elicit protective effects on AP. Importantly, Emo upregulates the expression of HINT2 and OXPHOS complex proteins and enhances the interaction between HINT2 and MTCO2. Furthermore, CRISPR/Cas9-mediated HINT2 knockout significantly impaired the protective effects of Emo against AP-induced mitochondrial energy metabolism disorders, inflammatory responses, and acinar cell necrosis. Overall, these results uncover a previously unexplored role for HINT2 in maintaining mitochondrial energy metabolism in pancreatic acinar cells and reveals novel mechanism and target for Emo-mediated AP remission.http://www.sciencedirect.com/science/article/pii/S1043661825000453Histidine triad nucleotide-binding protein 2Mitochondrial oxidative phosphorylationEmodinpancreatic acinar necrosisacute pancreatitis |
| spellingShingle | Jiaqi Yao Yuhong Jiang Pengcheng Zhang Yifan Miao Xiajia Wu Hang Lei Zhijun Xie Yong Tian Xianlin Zhao Juan Li Lv Zhu Meihua Wan Wenfu Tang Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis Pharmacological Research Histidine triad nucleotide-binding protein 2 Mitochondrial oxidative phosphorylation Emodin pancreatic acinar necrosis acute pancreatitis |
| title | Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis |
| title_full | Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis |
| title_fullStr | Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis |
| title_full_unstemmed | Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis |
| title_short | Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis |
| title_sort | genetic and pharmacological targeting of hint2 promotes oxphos to alleviate inflammatory responses and cell necrosis in acute pancreatitis |
| topic | Histidine triad nucleotide-binding protein 2 Mitochondrial oxidative phosphorylation Emodin pancreatic acinar necrosis acute pancreatitis |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825000453 |
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